VITAMIN D METABOLISM BY T CELL LYMPHOCYTES

这个项目的目的是描述维生素D的代谢 由T细胞产生的淋巴细胞在体外特别注意产生 1，25-二羟基维生素D(1，25(OH)2D)的最活跃代谢物 维生素D。首席调查员的初步结果 实验室研究表明，HTLV转化的脐带血淋巴细胞具有 将25(OH)D转化为更极性的代谢物的能力 使用两个单独的高效液体的正品1，25(OH)2D 层析系统并在体外刺激骨吸收。 气相色谱/质谱法鉴定该代谢物为1，25(OH)2D 光谱分析表明，这些转化的淋巴细胞 1-α-羟基酶活性。因为1，25(OH)2D是一种有效的刺激物 破骨细胞性骨吸收，增加1，25(OH)2D或其他 淋巴瘤细胞的维生素D代谢产物可能在发病机制中发挥作用 发生的破骨细胞性骨吸收增加和高钙血症 在这种疾病中。 因此，本研究的目的是使用HTLV转化 淋巴细胞作为研究维生素D代谢的体外模型 淋巴细胞，以便： 1.鉴定HTLV产生的维生素D代谢物 转化的T淋巴细胞，特别注意产生 1，25(OH)2D。 2.检测外周血淋巴细胞对维生素D的代谢 以淋巴细胞异常为特征的其他疾病状态的患者 功能和骨骼和矿物质代谢的改变。 3.确定激活的正常淋巴细胞是否有1-α-羟基酶 活动。 4.正常和异常状态下的1-α-羟基酶活性特征 淋巴细胞，看看它是否受到相同的调节因素的调节 肾脏1-α-羟基酶活性。 这些研究将决定是否有能力生产 1，25(OH)2D是所有激活的淋巴细胞的一般性质或是一种 感染HTLV病毒的淋巴细胞的独特性质。此外， 该1-α-羟基酶活性的表征和鉴定 那些调节淋巴细胞1-α-羟基酶活性的因素将 提供有关控制维生素D的因素的重要信息 正常个体和疾病状态下的代谢均表现为 骨骼和矿物质代谢异常。这些结果也将形成 旨在阐明相关分子机制的研究基础 用于激活淋巴细胞中的1-α-羟基酶活性。

The purpose of this project is to characterize the metabolism of vitamin D by T-cell lymphocytes in vitro with particular attention to the production of 1,25-dihydroxyvitamin D (1,25(OH)2D), the most active metabolite of vitamin D. Preliminary results from the Principal Investigator's laboratory indicate that HTLV-transformed cord blood lymphocytes have the capacity to convert 25(OH)D to a more polar metabolite which coelutes with authentic 1,25(OH)2D using two separate high performance liquid chromatography systems and stimulates bone resorption in vitro. Identification of this metabolite as 1,25(OH)2D by gas chromatography/mass spectrometry suggest that these transformed lymphocytes have 1-alpha-hydroxylase activity. Since 1,25(OH)2D is a potent stimulator of osteoclastic bone resorption, increased production of 1,25(OH)2D or other vitamin D metabolites by lymphoma cells may play a role in the pathogenesis of the increased osteoclastic bone resorption and hypercalcemia which occur in this disease. Accordingly, the purpose of this study is to use HTLV-transformed lymphocytes as an in vitro model to study the metabolism of vitamin D by lymphocytes in order to: 1. Characterize the metabolites of vitamin D which are produced by HTLV transformed T-lymphocytes with particular attention to the production of 1,25(OH)2D. 2. Examine the metabolism of vitamin D by peripheral lymphocytes in patients with other disease states characterized by abnormal lymphocyte function and altered bone and mineral metabolism. 3. Determine if activated normal lymphocytes have 1-alpha-hydroxylase activity. 4. Characterize the 1-alpha-hydroxylase activity in normal and abnormal lymphocytes to see if it is regulated by the same factors which regulate renal 1-alpha-hydroxylase activity. These studies will determine whether or not the ability to produce 1,25(OH)2D is a general property of all activated lymphocytes or is a unique property of lymphocytes infected with the HTLV virus. Moreover, characterization of this 1-alpha-hydroxylase activity and identification of those factors which regulate lymphocyte 1-alpha-hydroxylase activity will provide important information concerning factors that control vitamin D metabolism both in normal individuals and disease states characterized by abnormal bone and mineral metabolism. These results will also form the basis of studies designed to elucidate the molecular mechanisms responsible for the activation of 1-alpha-hydroxylase activity in lymphocytes.